Failure of cells to respond to DNA damage is a key mechanism of toxicity by environmental agents and a primary step in the onset of cancer. In this research program, we are using systematic approaches to map and model the genetic networks underlying the DNA damage response (DDR). Since DDR pathways are widely conserved, our studies bridge between Homo sapiens and the budding yeast Saccharomyces cerevisiae? impacting our knowledge of how genotoxic agents lead to pathogenesis in humans, coupled to a classic model organism for which new genetic technologies are readily developed and deployed. In the past five years of funding (NIH grant R01-ES14811), we made significant progress in identifying changes in yeast genetic, transcriptional, and signaling networks in response to DNA damage stress. We also developed innovative new technologies, including the experimental technique of ?differential? genetic interaction mapping and a computational approach to translate interaction networks into hierarchical, data-driven gene ontologies. In the next period of support, we will: (1) Significantly expand the yeast genetic interaction maps to include dynamic growth curves and specific DDR pathway readouts at high-throughput; (2) Develop and apply CRISPR technology to create parallel genetic network maps in human cell lines; and (3) Integrate all new and prior data to build comprehensive ontologies of DDR subsystems in yeast and human, which we will compare to systematically identify areas of conservation and divergence and validate specific DDR phenotypic predictions in mechanistic assays. This work moves us closer to a comprehensive structure/function model of the DDR. A growing set of DNA- damage-induced genetic networks and ontologies in model species and humans are important resources for understanding genetic polymorphisms that predispose an individual to environmental DNA damage and DDR- related diseases.